Neuroscience Seminar Series :
Valérie Mezger (Université Paris Diderot -CNRS, UMR7216 Épigénétique et Destin Cellulaire)
Fetal stress and epigenetic regulations in the normal and diseased developing brain
Video of the event (restricted to Paris descartes members).
We aim to understand the links between environmental stress and brain development and integrity. There is an almost complete black box between the observation that fetal stress is a factor of predisposition to brain disabilities and the resulting emergence of associated cognitive and affective disorders. In particular, the molecular mechanisms underlying the short- and long-term effects of fetal stress in the etiology of these disabilities are largely unknown.
We address this question by studying Heat Shock Factors that represent a unique entry point into a link between stress, epigenetics, and brain development/integrity. Importantly, we demonstrated that HSF2 is involved in brain cortical development.
Using fetal alcohol exposure (FAE) as a paradigm of prenatal stress in mouse models, we investigate whether HSFs could contribute to the deposition of short- and long-term epigenetic marks.
1) We showed that HSF2 is an essential mediator of neuronal migration defects characteristic of Fetal Alcohol Syndrome, in response to FAE in the developing brain.
2) We unravelled a dynamic interplay between HSF2 and HATs, quickly followed by interactions between HSF2 and HDAC1/2 during stress.
3) We unravelled a crosstalk between HSFs and the expression of epigenetic actors whose expression can be disturbed by stress in an HSF-dependent manner.
We are currently investigating how the HSF-dependent deposition of epigenetic marks upon fetal stress, via the formation of these complexes or disturbances in DNA methylation, is susceptible to lead to long-term disturbances of HSF2 target genes that are involved not only in neuronal migration, but also in brain abilities via the control of neurite growth and neuronal plasticity.